The present invention provides novel compounds. More particularly, the present invention provides novel peptide analogs and intermediates thereto. Most particularly, the present invention provides compounds having a (1-cyclohexylmethyl-1-amino-2-hydroxy-2-(2-pyrrolidinyl))ethyl end function. The peptides provided herein are useful as renin inhibitors and as inhibitors of retroviral proteases. Renin inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renin-dependent hyperaldosterism, and other renin-dependent cardiovascular disorders. Inhibitors of retroviral proteases, such as the HIV-I protease, are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS).
Renin is an endopeptidase which specifically cleaves a particular peptide bond of its substrate (angiotensinogen), of which the N-terminal sequence in equine substrate is for example: ##STR2## as found by L. T. Skeggs et al. J. Exper. Med. 106, 439 (1957). Human renin substrate has a different sequence as recently discovered by D. A. Tewkesbury et al, Biochem. Biophys. Res. Comm. 99, 1311 (1981). It may be represented as follows: ##STR3## and having the sequence to the left of the arrow (.dwnarw.) being as designated in formula IA above.
Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of angiotensin I converting enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin may also be useful in the treatment of hypertension.
A number of renin-inhibitory peptides have been disclosed. Thus, U.S. Pat. No. 4,424,207; European published applications 45,665; 104,041; and 156,322; and U.S. patent application Ser. No. 825,250, filed Feb. 3, 1986; disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; 114,993; 156,319; and 156,321; and U.S. Pat. Nos. 4,478,826; 4,470,971; 4,479,941; and 4,485,099. Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. Pat. Nos. 4,477,440 and 4,477,441. Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S. Pat. Nos. 4,478,827 and 4,455,303. Renin inhibitors containing a C-terminal amide cycle are disclosed in U.S. Pat. No. 4,485,099 and European published applications 156,320 and 156,318. Certain tetrapeptides are disclosed in European publications 111,266 and 77,027. Further, European published application No. 118,223 discloses certain renin inhibiting peptide analogs where the 10-11 peptide link is replaced by a one to four atom carbon or carbon-nitrogen link. Additionally, Holladay et al., in "Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isosteres", Tetrahedron Letters, Vol. 24. No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-directed "ketomethylene" and "hydroxyethylene" dipeptide isosteric functional groups disclosed in the above noted U.S. Pat. No. 4,424,207. Evans, et al., J. Org. Chem., 50, 4615 (1985) discloses the synthesis of Hydroxyethylene Dipeptide Isosteres. See also, published European patent application 163,237, which discloses certain renin inhibitoring peptides.
Additionally, published European Applications 45,161 and 53,017 disclose amide derivatives useful as inhibitors of angiotensin converting enzymes.
Certain dipeptide and tripeptides are disclosed in U.S. Pat. Nos. 4,514,332; 4,510,085; and 4,548,926 as well as in European published applications 128,762; 152,255; and 181,110. Pepstatin derived renin inhibitors have been disclosed in U.S. Pat. No. 4,481,192. Retroinverso bond modifications at positions 10-11 have been disclosed in U.S. Pat. No. 4,560,505 and in European published applications 127,234 and 127,235. Derivatives of isosteric bond replacements at positions 10-11 have been disclosed in European published applications 143,746 and 144,290; and U.S. patent application Ser. No. 904,149, filed Sep. 5, 1986. Isosteric bond modifications at positions 11-12 and 12-13 have been disclosed in European published application 179,352. Certain peptides containing 2-substituted statine analogues have been disclosed in European published application 157,409. Certain peptides containing 3-aminodeoxystatine have been disclosed in European published application 161,588. Certain peptides containing 1-amino-2-hydroxybutane derivatives at positions 10-11 have been disclosed in European published application 172,346. Certain peptides containing 1-amino-2-hydroxypropane derivatives at positions 10-11 have been disclosed in European published application 172,347. Certain peptides containing N-terminal amide cycles have been disclosed in U.S. patent application Ser. No. 844,716, filed Mar. 27, 1986. Certain peptides containing dihalostatine have been disclosed in PCT application, Ser. No. 000,713, filed Apr. 7, 1986. Certain peptides containing C-terminus truncated epoxy or azido or cyano groups or containing a position 10-11 diol and a position 11-12 retro bond have been disclosed in U.S. patent application Ser. No. 945,340, filed Dec. 22, 1986.
European published applications 156,322; 114,993; and 118,223; and PCT patent application, Ser. No. 002,227, filed Nov. 21, 1986; U.S. patent application Ser. No. 825,250, filed Feb. 3, 1986; U.S. patent application Ser. No. 904,149, filed Sep. 5, 1986; and U.S. patent application Ser. No. 844,716, filed Mar. 27, 1986; disclose hydroxamic acids or esters at the C-terminus.
E.P. 189,203 discloses new N-dihydroxyalkyl peptide derivatives which are useful as inhibitors of renin for treating hypertension.
E.P. 184,855 discloses new hydroxy substituted-statine peptide derivatives which are useful as inhibitors of renin for treating hypertension.
Derivatives of isosteric bond replacements at positions 10-11 as dihydroxy ethylene isosteres have been disclosed in U.S. patent application Ser. No. 904,149, filed Sep. 5, 1986.
A review of the theoretical principles of such transition-state mimetics of renin inhibitors have been recently reviewed in D. H. Rich, Chapter 5, "Inhibitors of Aspartic Proteinases," Proteinase Inhibitors, Elsevier Science Publishers BV (Biochemical Division) (1986).
The following references disclose additional substituents at the 10, 11-position: A. Spaltenstein, P. Carpino, F. Miyake and P. B. Hyskins, Tetrahedron Letters, 27:2095 (1986); D. H. Rich and M. S. Bernatowicz, J. Med. Chem., 25:791 (1982); Roger, J. Med. Chem., 28:1062 (1985); D. M. Glick et al., Biochemistry, 21:3746 (1982); D. H. Rich, Biochemistry, 24:3165 (1985); R. L. Johnson, J. Med. Chem., 25:605 (1982); R. L. Johnson and K. Verschovor, J. Med. Chem., 26:1457 (1983); R. L. Johnson, J. Med. Chem., 27:1351 (1984); P. A. Bartlett and W. B. Kezer et al., J. Am. Chem. Soc., 106:4282 (1984); Peptides: Synthesis, Structure and Function (V. J. Hruby; D. H. Rich, eds.) Proc. 8th American Peptide Sym., Pierce Chemical Company, Rockford, Ill., pp. 511-20; 587-590 (1983).
The preparation of cyclopropyl-containing renin inhibiting peptides is disclosed in U.S. patent application Ser. No. 023,404, filed Mar. 9, 1987, which is incorporated by reference herein.